Abstract

Background A number of functional brain abnormalities have been
reported in schizophrenia, but it remains to be determined which of them
represent trait and state markers of the illness.

Aims To delineate regional brain dysfunctions that remain stable and
those that fluctuate during the course of schizophrenia.

Method A cohort of patients with first-episode schizophrenia and a
matched group of control participants underwent functional magnetic resonance
imaging on two occasions 6–8 weeks apart during performance of a working
memory task. The patients’ disease was in partial remission at the
second scan.

Results Relative to control participants, the function of the left
dorsolateral prefrontal cortex, left thalamus and right cerebellum remained
disturbed in the people with schizophrenia, whereas the dysfunction of the
right dorsolateral prefrontal cortex, right thalamus, left cerebellum and
cingulate gyrus normalised, with significant reduction in symptoms.

Conclusions These results suggest that dysfunction of the left
fronto-thalamo-cerebellar circuitry is a relatively stable characteristic of
schizophrenia, whereas disturbance of the right circuitry and cingulate
gyrusis predominantly a state-related phenomenon.

Many abnormalities of regional brain activity have been reported in
schizophrenia (Liddle, 2000),
but there is little consensus as to which abnormalities are stable and thus
potential trait markers, and which are transient markers of current clinical
state. In a recently completed study we observed that relative to control
participants, clinically stable, medicated people with schizophrenia exhibited
abnormal activity in the dorsolateral prefrontal cortex, cingulate gyrus and
cerebellum during performance of the ‘N-back’ working memory task
(Mendrek et al,
2004). These results provided partial support for both the ‘
cognitive dysmetria’ model of schizophrenia, which suggests that
reduced activation in the fronto-thalamo-cerebellar circuitry is a core
pathophysiological feature of the illness
(Andreasen, 1999), and for the
proposition that corticolimbic system dysregulation has a significant role in
the formation of psychotic symptoms (Benes,
2000). The study reported here was designed to explore the pattern
of cerebral function in a group of patients with first-episode schizophrenia
during two stages of their illness – acute psychosis and partial
remission – in order to determine which elements of the distorted
circuitry are stable over time and which fluctuate with change in clinical
state. Based on recent theories and empirical findings in schizophrenia
research (Lahti et al,
1995; Andreasen et al,
1996; Crespo-Facorro et
al, 1999; Holcomb et
al, 2000), our hypothesis was that the disturbance of
fronto-thalamo-cerebellar circuitry in patients with first-episode
schizophrenia would remain under-activated over time, whereas the function of
the cingulate gyrus would vary with changes in clinical status.

METHOD

Participants

Ten people with first-episode schizophrenia, recruited within a week of
their admission to the psychiatric ward of the University of British Columbia
Hospital in Vancouver, participated in the study. All patients were judged by
the attending physicians to be competent to give informed consent and capable
of cooperating during the imaging procedure. All patients initially diagnosed
as having a brief psychotic disorder, schizophreniform disorder or
schizophrenia were subsequently given a diagnosis of schizophrenia according
to DSM–IV criteria (American
Psychiatric Association, 1994). Patients underwent a functional
magnetic resonance imaging (fMRI) brain scan during their first week of
antipsychotic treatment and were scanned again after a further 6–8 weeks
of treatment. The first scan took place after approximately 3 days of
antipsychotic treatment to minimise the problem of acute agitation during the
procedure although initial dosages were low to avoid excessive sedation.
Patients were treated with atypical antipsychotic medication (either
risperidone or olanzapine) throughout the study, at a dose judged to be
optimal on clinical grounds. As a result of the study design, we were unable
to detect the immediate consequences of antipsychotic treatment; on the other
hand, because patients were receiving similar medication during the first and
second scanning sessions, the observed systematic changes in brain function
are likely to reflect the gradual changes in clinical status during sustained
treatment, rather than immediate pharmacological effects. The data obtained
from two patients were discarded from the final analysis because of failure to
meet the predetermined acceptable level of accuracy in the task performed
during scanning. At the beginning of the study, seven of the remaining eight
patients were receiving treatment with risperidone (mean daily dosage 3 mg,
s.d.=0.4) and one was taking olanzapine (10 mg); at the end of the study,
seven were taking risperidone (mean daily dosage 2.7 mg, s.d.=0.3), two were
taking olanzapine (mean daily dosage 12.5 mg, s.d.=2.5) and one patient was
receiving both medications (1 mg risperidone and 10 mg olanzapine).

In addition to an interview and a review of case notes to corroborate the
diagnosis of schizophrenia and assess changes in symptoms over time, all
patients were assessed with the Signs and Symptoms of Psychotic Illness scale
(SSPI; Liddle et al,
2002), which measures the severity of 20 signs and symptoms of
acute and chronic psychotic illness; a score of 18 (s.d.=7) is typical of an
acute psychotic state (Liddle et
al, 2002). The group of patients in our study obtained a mean
score of 19.85 (s.d.=10.72) during the first assessment with the SSPI (within
the first week of treatment) and a mean score of 13.0 (s.d.=10.78) during the
second assessment (after 6–8 weeks of treatment).

The group of eight healthy control participants, with no current or past
psychotic illness and no psychotic illness in a first-degree relative, did not
differ from the group of patients in terms of age, gender, parental
socio-economic status or IQ (Table
1). Parental socio-economic status was assessed using the
Hollingshead criteria for parental social position
(Hollingshead & Redlich,
1958) and IQ was measured using the Quick test
(Ammons & Ammons, 1962).
All participants were right-handed according to the Annett Handedness scale
(Annett, 1970). The study was
approved by the ethics review committee of the University of British Columbia.
All participants gave written consent after the experimental details were
explained to them.

Behavioural test and data analysis

The behavioural task used in our study was one used previously in
neuroimaging investigations of working memory
(Awh et al, 1996;
Cohen et al, 1997;
Jonides et al, 1997).
This version of the n-back task consisted of a screen display of a
succession of letters; the person tested was required to press a button
whenever the designated letter appeared. In our study, participants either had
to press the button whenever the letter X appeared (the ‘0-back’
task) or press it any time they saw a letter identical to one presented two
screens earlier (the ‘2-back’ task). Each letter was displayed for
a duration of 250 ms with an inter-stimulus interval of 2 s. Participants were
required to complete two runs of alternating 30 s periods of 0-back and 2-back
testing, separated by 20 s rest periods; each run lasted about 7 min. Both
tasks involved similar sensory processing of information and a similar amount
of motor activity. Before scanning, participants were given full instructions
and a 3 min practice session, in which they had to reach a 70% accuracy level.
Despite successful practice, two patients failed to reach the required 60%
level of accuracy during performance of the task in the scanner and their data
were discarded from the analysis. All participants performed the task on two
separate occasions, 6–8 weeks apart.

The behavioural data were analysed using between–within repeated
measures, condition (0-back, 2-back) by group (patients, controls) by scanning
session (first, second), factorial analyses of variance (ANOVAs). Separate
ANOVAs were used to evaluate performance accuracy and reaction time data.
Errors of omission were defined as a failure to respond to the target stimulus
within 1500 ms of stimulus onset; errors of commission were defined as a
response to a non-target stimulus within the same time frame.

The statistical analyses were performed using a random effects model as
implemented in SPM99 for UNIX. In the computation of this analysis, first the
observed time courses of image intensities were temporarily filtered to remove
noise associated with low-frequency confounds such as respiration. In
addition, each type of epoch (i.e. 2-back, 0-back and rest) was modelled by a
boxcar waveform with a temporal delay of 6 s to account for the relatively
slow onset of the haemodynamic response. Then, single images for each
participant in each session were created based on the 2-back v.
0-back and 0-back v. rest contrasts. These contrast images were
subsequently entered into a second-level random-effects analysis, which
employed t-tests to assess the significance of the planned
comparisons between conditions and between groups. The mean difference in
cerebral activation between the 2-back and 0-back conditions and the
difference between the 0-back and rest condition within each group and within
each scanning session were assessed using one-sample t-tests. These
analyses were performed for the entire brain volume at the cluster level
(P≤0.05 corrected for multiple comparisons, thresholded at
P≤0.001) as implemented in SPM99
(Friston et al,
1994). The differences between groups in the contrast between
2-back and 0-back and between 0-back and rest in each session were assessed
using two-sample t-tests. In addition to the search in the entire
brain volume for the within-group analysis, in order to increase statistical
sensitivity and to reduce the probability of type 2 error in assessing our
hypothesis regarding the fronto-thalamo-cerebellar and corticolimbic systems,
the between-group as well as the within-group between-session comparisons were
restricted to voxels contained within predefined regions of interest. These
regions of interest were eight spheres 12 mm in radius centred on the loci of
peak activation in the brain regions relevant to our hypothesis (previously
identified in a pilot study of a separate group of 11 healthy volunteers),
sited in the bilateral dorsolateral prefrontal cortex, bilateral thalamus,
bilateral cerebellum and the anterior and posterior cingulate gyrus
(Table 2). In testing for the
significance of changes in these regions, we applied the criterion of
P≤0.005. In order to avoid global normalisation artefacts
(Andersson, 1997;
Aguirre et al, 1998;
Desjardins et al,
2001), this procedure was not performed.

Talairach coordinates of maximally activated voxels during the 2-back
v. 0-back condition by 11 healthy volunteers in the pilot
study

RESULTS

Behavioural data

The paired t-tests revealed that in the schizophrenia group the
participants’ symptoms, assessed using the SSPI scale during the first
week of treatment, diminished significantly after 6–8 weeks of
antipsychotic medication: t(7)=9.26, P<0.001.
The between–within repeated measures factorial ANOVA for the errors of
omission during performance of the working memory task in two scanning
sessions showed that patients performed significantly worse than control
participants (main effect of group, F(1, 14)=14.1,
P<0.01) and that both groups made significantly fewer errors in
the 0-back task than in the 2-back task (main effect of condition,
F(1, 14)=21.58, P<0.001). There was no group ×
condition interaction (P>0.05) but a statistically
significant condition × scanning session interaction (F(1,
14)=6.96, P<0.05) was present, reflecting a reduction in
error rate during the second scanning session. The performance accuracy is
illustrated in Fig. 1. The
separate ANOVA for the errors of commission did not reveal any statistically
significant results. Finally, the ANOVA of reaction time data showed that it
took significantly longer to respond correctly in the 2-back task than in the
0-back task (main effect of condition, F(1, 14)=48.52,
P<0.001) and that patients were slower at responding than were
control participants (main effect of group, F(1,
14)=30.02, P<0.001). A significant group × condition
interaction was also present (F(1, 14)=7.3,
P<0.05).

Mean number of errors of omission by first-episode patients (squares) and
control participants (circles) during the n-back task in the first
(solid lines) and second (dashed lines) scanning sessions.

Imaging data

The analyses of the pattern of cerebral activity during the 2-back
v. 0-back condition in healthy participants demonstrated significant
activations in bilateral prefrontal, premotor and parietal cortex, as well as
in bilateral cerebellum and thalamus (Table
3, Fig. 2a). The
0-back v. rest comparison revealed significant findings in the
supplementary motor area, but not in any of the above-mentioned regions
implicated in a working memory function
(Table 3,
Fig. 2b). The same pattern of
activity was apparent in these participants, during the second scanning
session 6–8 weeks later (Table
3, Fig. 2c, d).

In contrast, the comparison between the 2-back and 0-back tasks in the
acutely ill patients revealed activation only in a few isolated clusters of
the prefrontal and parietal cortex (Table
4, Fig. 3a).
Analysis of 0-back v. rest demonstrated significant and widespread
pattern of activations in the bilateral prefrontal and parietal cortex,
thalamus and cerebellum (Table
4, Fig. 3b). This ‘
shifted’ pattern of activity, with extensive activation during
the 0-back task relative to rest and minimal increase in activation from
0-back to 2-back, normalised over time with treatment, although not
completely. Thus, after 6–8 weeks of treatment, accompanied by a
significant improvement in symptoms, the activation during the 0-back
v. rest condition diminished
(Table 4,
Fig. 3c) and the activation of
2-back v. 0-back had increased
(Table 4,
Fig. 3d).

The above phenomenon is illustrated by the magnitude of activation of the
left dorsolateral prefrontal cortex in the different conditions in the two
groups of participants (Fig.
4). Thus, healthy participants showed no activation of this brain
area during the 0-back task but significant activation during the 2-back task,
resulting in a highly significant difference between the two conditions. In
comparison, patients with acute psychosis activated dorsolateral prefrontal
cortex to a comparable level during both tasks, resulting in a non-significant
difference between the two. In effect, the patients exhibited relative
hyperfrontality during the 0-back task compared with controls. Importantly, at
this session they did not achieve the magnitude of activation present in
healthy participants during the 2-back task. In patients in remission the
difference in dorsolateral prefrontal cortex activation was detectable between
the two test conditions, but again this brain area did not attain the levels
of activity apparent in controls during the 2-back task.

Left dorsolateral prefrontal cortex activation during the 2-back and 0-back
tasks v. rest in the two scanning sessions.

The between-group analysis of data obtained during the first scanning
session revealed that in comparison with control participants, patients
exhibited less activity in the specified regions of interest in the bilateral
dorsolateral prefrontal cortex, thalamus, cerebellum and posterior cingulate
cortex during the 2-back v. 0-back condition. In contrast, the
comparison between 0-back and rest revealed greater activity in patients
relative to controls in all of the above structures except the left thalamus
and right cerebellum (Table 5).
The between-group analysis of data obtained at the second scanning session
revealed that patients exhibited less activity in specified regions of
interest in the left dorsolateral prefrontal cortex, left thalamus and right
cerebellum during the 2-back v. 0-back condition and relatively more
activity in the left dorsolateral prefrontal cortex during 0-back v.
rest (Table 5).

Areas of significant difference between patient and control groups
during task performance based on random-effects analysis in eight regions of
interest (P≤0.005)

Finally, the comparison of regions of interest between the first and second
scanning sessions in healthy participants did not reveal any significant
differences, whereas the same comparison in patients revealed significant
changes in the activation pattern over time in the right dorsolateral
prefrontal cortex, right thalamus, left cerebellum and posterior cingulate
(Table 6).

Areas of significant difference between patients’ first and
second scanning sessions during task performance, based on random-effects
analysis in eight regions of interest (P≤0.005)

DISCUSSION

Principal within-group findings

The results obtained in the group of healthy participants were consistent
with our previous findings (Mendrek et
al, 2004) and with other studies of working memory function
in healthy volunteers (D’Esposito
et al, 1995; Awh
et al, 1996; Cohen
et al, 1997; Jonides
et al, 1997). Thus, the healthy participants exhibited
widespread activation in the bilateral prefrontal cortex, parietal cortex,
thalamus and cerebellum during the 2-back task v. 0-back condition,
and significant activation in a circumscribed region of supplementary motor
area during 0-back v. rest (see
Fig. 2,
Table 3). In marked contrast,
the participants with acute psychosis exhibited little activation during the
2-back v. 0-back condition, but extensive activation during 0-back
v. rest condition in several of the areas activated in control
participants during the 2-back task – namely the bilateral prefrontal
cortex, parietal cortex, thalamus and cerebellum (see
Fig. 3,
Table 4). Thus, the lack of
substantial difference between 2-back and 0-back arose from the fact that both
tasks produced similar patterns of neural activation in patients with acute
psychosis; in other words, the normally undemanding 0-back task was
challenging enough for patients to recruit the available cerebral resources to
near-maximal capacity, so that there was no possibility of enhancing cerebral
function during the 2-back task. The finding of augmented cerebral activation
during the 0-back condition is congruent with previous neuroimaging studies in
which various working memory tasks enhanced prefrontal cortex activation in
patients who performed above the chance level but worse than a control group
(Manoach et al, 1999,
2000;
Callicott et al,
2000). It is also consistent with the report by Ramsey et
al (2002), who suggested
that the inefficiency of neural communication in schizophrenia results in
excessive recruitment of neural systems in patients relative to control
participants during comparable performances on cognitive tasks.

The pattern of neural activation during performance of the n-back
task normalised to some extent over time with antipsychotic treatment and
improvement in the clinical state of the patients. Thus, in the second
scanning session, patients did not exhibit any anomalous overactivation during
the 0-back v. rest condition, but the level of cerebral activation
observed during the 2-back v. 0-back condition was still diminished
relative to control participants.

Principal between-group findings

The between-group region of interest analyses confirmed and extended the
within-group results. Compared with control participants, patients with acute
psychosis exhibited significant underactivation bilaterally in the
dorsolateral prefrontal cortex, cerebellum, thalamus and posterior cingulate
in the 2-back v. 0-back condition, while showing overactivation in
all of these regions (with the exception of right cerebellum and left
thalamus) during 0-back v. rest. The relative underactivation during
the 2-back task coupled with the lack of overactivation during the 0-back task
implies true underutilisation of the right cerebellum and left thalamus in
acute psychosis (as opposed to maximal activation during 0-back and no
additional increase during the 2-back task). Moreover, both right cerebellum
and left thalamus remained underused in the second scanning session in
patients with partially remitted disease relative to control participants,
pointing to the stable nature of this disturbance. This interpretation is
supported by the observation of a similar pattern of decreased activation in
clinically stable, medicated patients
(Mendrek et al,
2004). Nevertheless, it must be emphasised that our findings
cannot exclude significant effects on regions outside the set of preselected
regions of interest.

Like the right cerebellum and left thalamus, the left dorsolateral
prefrontal cortex also remained functionally suppressed, although to a lesser
degree (see below and Fig. 4
for explanation of this anomaly). In contrast, activation of the right
dorsolateral prefrontal cortex, right thalamus, left cerebellum and posterior
cingulate normalised over time with antipsychotic treatment and attenuation of
symptoms, to a level that was not significantly different from that in the
healthy group, suggesting that disturbance of these sites represents a state
marker for acute exacerbation of schizophrenia.

The question of changes in the pattern of cerebral activity accompanying
the resolution of psychosis was also addressed with the between-session
analysis of the patients with schizophrenia, which revealed significant change
in activation over time in the right dorsolateral prefrontal cortex, right
thalamus, left cerebellum and posterior cingulate. It is important to point
out that in these patients the disease was in partial rather than full
remission during the second scanning session, and further normalisation of
function of these structures could be anticipated with the complete resolution
of symptoms.

Lateralisation effect

Overall, the results revealed that the more persistent abnormalities of the
acute psychotic state were localised in the left cerebral hemisphere and right
cerebellum, whereas more transient features were localised in the right
cerebral hemisphere and left cerebellum. However, again it is essential to
point out that this conclusion is restricted to areas that were included in
the region of interest analysis. The observed relationship between cerebral
and cerebellar abnormalities is consistent with existence of contralateral
connections between the dorsolateral prefrontal cortex and cerebellum relayed
by thalamic nuclei (Middleton &
Strick, 2001). Accordingly, the concurrent dysfunction of the
dorsolateral prefrontal cortex, cerebellum and thalamus in our schizophrenia
group may represent underlying disturbance in the connectivity between these
structures. This finding, together with other reports (e.g.
Andreasen et al, 1996;
Wiser et al, 1998;
Crespo-Facorro et al,
1999), provides support for the ‘cognitive dysmetria’
theory of schizophrenia (Andreasen,
1999), while the presence of lateralisation effect adds a new
layer of complexity to the model. Moreover, the observation of more persistent
abnormalities in the left hemisphere is in line with evidence from structural
abnormality studies in schizophrenia, in which most of the studies that found
significant asymmetry reported greater abnormality in the left hemisphere
(Hopkins & Lewis, 2000).
The persistence of the left hemisphere abnormalities and the transience of the
right hemisphere abnormalities during performance of the n-back task
are also broadly consistent with the hemispheric imbalance model proposed by
Gruzelier (1984). On the basis
of evidence from electrophysiological studies, Gruzelier proposed that in
schizophrenia symptoms reflecting excitation (which tend to be transient) are
associated with right hemisphere dysfunction, whereas symptoms reflecting
withdrawal (which tend to be more persistent) are associated with relative
underactivity of the left hemisphere.

Prefrontal cortex findings

Our results shed new light on the debate regarding prefrontal function in
schizophrenia (Weinberger & Berman,
1996; Manoach,
2003) and may help to reconcile the inconsistent findings of a
number of fMRI studies, some of which demonstrated diminished prefrontal
activation during working memory tasks in people with schizophrenia relative
to control participants (Callicott et
al, 1998; Carter et
al, 1998; Stevens et
al, 1998; Perlstein
et al, 2001), whereas others found enhanced activation
(Manoach et al, 1999,
2000;
Callicott et al,
2000) or no difference between the groups
(Honey et al, 2002).
We observed both overactivation of the prefrontal cortex during the 0-back
task and underactivation during the 2-back task in patients relative to
controls. This finding fits well with empirical evidence of a nonlinear,
inverted U-shaped response in dorsolateral prefrontal cortex function to
parametrically increasing working memory difficulty. Thus, in healthy
volunteers dorsolateral prefrontal cortex activation increases together with
the working memory load; but although the initial reduction in working memory
capacity may be associated with relative overactivation of this brain region
(Rypma & D’Esposito,
1999), further decline in the capacity to process information is
accompanied by its relative underactivation
(Callicott et al,
1999). Manoach
(2003) has proposed that this
inverted U-shaped function is shifted to the left in people with
schizophrenia, such that the increase, plateau and eventual decrease in
activation can be observed with lower working memory loads than in healthy
individuals. Our data suggest that in addition to this leftwards shift there
might be also a downwards shift in dorsolateral prefrontal cortex function in
schizophrenia. Specifically, although prefrontal dysfunction in the patient
group was modulated to a certain degree by clinical status and the type of
presented challenge, there appears also to exist a persistent abnormal
limitation of left dorsolateral prefrontal cortex activation in schizophrenia.
This limitation might be related to structural anomaly of this region in
schizophrenia reported by Selemon et al
(1995) and Rajkowska et
al (1998).

Present results in the light of previous longitudinal studies

This study is one of the first longitudinal investigations of a cohort of
patients at two different stages of their illness, a study design that has
become more feasible with the widespread availability of non-invasive fMRI
technology. Partly because of the challenging nature of these studies, only a
few such reports in schizophrenia have been published
(Honey et al, 1999;
Manoach et al, 2001;
Stephan et al, 2001).
Honey et al (1999)
demonstrated that after switching from typical to atypical antipsychotic
medication, patients exhibited increased prefrontal and parietal activation
during a working memory task. Stephan et al
(2001) tested two groups of
people with schizophrenia, one drug-free and one treated with olanzapine and
found that the pharmacological treatment normalised cerebellar functional
connectivity during a simple motor task. Manoach et al
(2001) studied
test–retest reliability of working memory performance in clinically
stable patients with schizophrenia and in healthy volunteers and found that
even given reliable task performance and a stable clinical status, individual
participants showed variability in cerebral activation, although the
group-averaged activation pattern did not differ between the first and second
scanning sessions.

Study limitations

Our results are subject to some limitations. For example, the fact that
patients were treated throughout the course of the study with antipsychotic
medication does not allow us to distinguish changes in brain function
attributable to long-term primary pharmacological effects from changes
attributable to alteration in clinical state. Specifically, some of our
results might be interpreted as evidence that medication ameliorates
abnormality in one network (right fronto-thalamo-cerebellar) but not in
another (left fronto-thalamo-cerebellar). However, we consider it unlikely
that all of the effects we observed reflect the effects of medication. In
particular, the differences between patients and controls in the first
scanning session are unlikely to be due to medication, as these differences
were in the opposite direction to the changes that occurred during sustained
medication. Moreover, the differences between the groups in cerebral
activation could have arisen partly through the significantly inferior
performance on the n-back task of patients relative to control
participants. However, although the behavioural differences could have
partially contributed to the differential pattern of cerebral activations,
overall this explanation is too simplistic, because the performance of
patients was inferior on both the 0-back and the 2-back tasks, whereas
cerebral activation was increased in the first task and decreased in the
second. Furthermore, although the patients’ working memory did improve
between the first and second scanning sessions, there was no significant
correlation between change in the task performance and cerebral activity.
Finally, since we specifically investigated working memory we cannot draw any
conclusion about the functional substrates of other cognitive processes.

To summarise, the overall findings of our study suggest that
underutilisation of the left dorsolateral prefrontal cortex, left thalamus and
right cerebellum represents a stable, potential trait marker of schizophrenia,
whereas disturbances in the right dorsolateral prefrontal cortex, right
thalamus, left cerebellum and cingulate gyrus are a state-related
phenomenon.

Clinical Implications and Limitations

Clinical Implications

Underactivations of the left dorsolateral prefrontal cortex, left thalamus
and right cerebellum represent a stable potential trait marker of
schizophrenia.

Abnormalities in the right dorsolateral prefrontal cortex, right thalamus,
left cerebellum and cingulate gyrus normalise with improvement in clinical
status and thus represent a state-related phenomenon.

Identification of trait-related abnormalities could contribute to
development of more reliable diagnosis of schizophrenia, whereas
identification of state-related changes might help in evaluation of treatments
for schizophrenia and/or may serve as predictors of treatment outcome.

Limitations

The findings cannot exclude significant effects on regions outside of the
set of preselected regions of interest.

Patients were treated throughout the course of the study with antipsychotic
medications and changes in brain function attributable to pharmacological
effects cannot be distinguished from changes attributable to change in
clinical state.

Because we studied patients with the specific task of working memory we
cannot draw any conclusions about the functional substrates of other cognitive
processes.

Acknowledgments

The study was supported by grants from the Medical Research Council of
Canada and the Norma Calder Schizophrenia Research Foundation, and took place
at the Department of Psychiatry of the University of British Columbia. The
assistance of Drs Bruce Forster, Alex MacKay and Andra Smith and the
invaluable help of magnetic resonance imaging technicians Jennifer McCord,
Sylvia Rennenberg and Trudy Shaw and research assistant Cameron Anderson are
gratefully acknowledged. We also thank all those who participated in the
study.

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(1999) Differences in frontal cortical activation by a
working memory task after substitution of risperidone for typical
antipsychotic drugs in patients with schizophrenia. Proceedings of
the National Academy of Sciences of the USA,
96, 13432
-13437.

Rypma, B. & D’Esposito, M. (1999) The
roles of prefrontal brain regions in components of working memory: effects of
memory load and individual differences. Proceedings of the National
Academy of Sciences of the USA, 96, 6558
-6563.